Schizophrenia is the most serious and most harmful disease among all mental illnesses. The global morbidity is about 1-2%. The lifetime prevalence of schizophrenia patients is 0.7-0.8%, which is not significantly relevant to gender, race, or social boundaries. Meanwhile, the mortality of schizophrenia patients is 2-3 times higher than that of the general population. Recent studies have shown that the social burden of mental illness ranks first among diseases in China, exceeding diseases such as cardiovascular, respiratory diseases and malignant tumors.
There are two major types of drug for schizophrenia, i.e. “typical” anti-schizophrenia drug and “non-typical” anti-schizophrenia drug. Typical anti-schizophrenia drug (e.g. chloropromazine and haloperidol) which blocks dopamine D2 receptor has good therapeutic effect on positive symptoms of schizophrenia. But due to the strong blocking on dopamine D2 receptor, it will lead to side effects like extrapyramidal system (EPS) reaction, tardive dyskinesia and increase of prolactin. Furthermore, it is not effective for negative symptoms of schizophrenia.
Non-typical anti-schizophrenia drug represented by clozapine and risperidone has strong effect on not only dopamine (D2) receptor, but also 5-hydroxytryptamine (5-HT2A) receptor. These drugs provide significant advantages over typical anti-schizophrenia drug: good therapeutic effect against schizophrenia positive symptoms, significantly reduced side effects of extrapyramidal system reaction and tardive dyskinesia or the like, and some non-typical anti-schizophrenia drugs can improve the negative symptoms and cognitive disorders in some degree. However, all the non-typical anti-schizophrenia drugs in current clinical application have side effects of extended QT interval, hyper-prolactine or the like in varying degrees. Therefore, it is important to find a new drug which can effectively cure schizophrenia, and has less side effects.
Studies have shown that receptors like D2, 5-HT1A, 5-HT2A and H1 play a very important role in schizophrenia. Action with D2 receptor may be effective for the treatment of schizophrenia positive symptoms. The pyramidal neurons and GABA interneurons of prefrontal cortex comprise 5-hydroxytryptamine receptor 5-HT1A and 5-HT2A. 5-hydroxytryptamine system plays an important role in modulating the function of prefrontal cortex, including emotion control, cognitive behavior and working memory. 5-HT1A is associated with the effect of non-typical anti-psychosis drug therapy, which can improve negative symptoms and cognitive disorders. 5-HT2A receptor relates to various aspects, including cognition, emotion regulation and motion control. The blocking of 5-HT2A receptor can normalize the release of dopamine, exerting the effect of anti-psychosis. mRNA of 5-HT7 receptor is expressed in peripheral tissue as well as the central nervous system, wherein it is mainly located in thalamus, hypothalamus, cerebral cortex, hippocampus and amygdala. This receptor can modulate body temperature, biological rhythm, sleeping, emotion, learning and memory. 5-HT7 receptor is important for the modulation of central nervous system activities in normal and pathologic conditions, and can be utilized as an important target for mental disease treatment. Meanwhile, during long-term medication for schizophrenia treatment, some drugs are liable to bring about the side effect of bodyweight gain. Studies have shown that these side effects are closely related with histamine H1 receptor.
Therefore, it is desirable for novel anti-schizophrenia drug to have multiple receptors binding, broad range of activity, and reduced side effects of EPS and bodyweight gain or the like.